Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ncn(-c2ccccn2)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2ncn(-c3ccccn3)n2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2-(3-Bromo-1H-1,2,4-triazol-1-yl)pyridine (0.25 g, 1.12 mmol) and 3-chlorophenylboronic acid (0.35 g, 2.23 mmol) were dissolved in toluene (20 mL) and methanol (2 mL), then deoxygenated via argon bubbling for 10 min. Potassium carbonate (0.23 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium (129 mg, 0.11 mmol) were added to this stirred solution. The reaction container was fitted with a reflux condenser and stirred at 90° C. for 16 h, after which time it was cooled to ambient temperature and poured into a separatory funnel containing EtOAc (100 mL). The EtOAc solution was washed with H2O (2×100 mL), then brine (100 mL) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was chromatographed on silica gel eluting with hexanes:EtOAc (8:2) to afford 2-[3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl]pyridine as a white powder which was dissolved in dichloromethane (10 mL) and precipitated as the hydrochloride salt (M.p.=125–128° C.) upon treatment with 1M HCl in diethyl ether (1 mL).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:25]([C:29]([NH:31][C:32]5[C:37]([CH2:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=5[CH2:40][CH3:41])=[O:30])=[N:26][N:27]([CH3:28])[C:18]=4[C:17]=3[N:16]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:42][NH2:43]>O1CCCC1.ClCCl.CO>[ClH:1].[CH2:38]([C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:40][CH3:41])[C:32]=1[NH:31][C:29]([C:25]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][NH:43][CH3:42])(=[O:7])=[O:6])[CH2:9][CH2:10]4)=[N:16][C:17]=3[C:18]=2[N:27]([CH3:28])[N:26]=1)=[O:30])[CH3:39]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(S(=O)(=O)CCCCl)CC3)nc1-2
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(S(=O)(=O)CCCNC)CC3)nc1-2
Product: Cl
Temperature: 60 °C
Yield: 76 %

Procedure:
To a solution of 8-({1-[(3-chloropropyl)sulfonyl]piperidin-4-yl}amino)-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (30 mg, 0.050 mmol) in tetrahydrofurane (2 mL) in a sealed tube, methylamine (40% aqueous solution) (0.5 mL) was added. The mixture was then heated at 60° C. for 20 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 8/2) to 23 mg of the title compound (76% yield).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1C=CC=C[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]#[CH:11])#[CH:8].[C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C#Cc1ccccc1
Product: C#Cc1ccccc1C#C
Reaction time: 2 h

Procedure:
A copolymer prepolymer of diethynylbenzene and phenylacetylene was prepared in refluxing benzene solvent. The polymerization vessel was charged with 60 parts of a 90:10 mixture of m- and p-diethynylbenzenes, 60 parts of phenylacetylene, 600 parts of benzene and 2 parts of chlorobenzene. After heating to reflux, 5 parts of a catalyst solution prepared by adding 0.3 part of nickel acetylacetonate and 0.6 part of triphenylphosphine in 15 parts benzene were added. After 2 hours, an additional 10 parts of this catalyst solution was added. After 5 hours, gas-liquid chromatographic analysis showed that 74% of the diethynylbenzenes and 35% of the phenylacetylene had been converted to copolymer. The copolymer was precipitated by adding the solution to five times its volume of petroleum ether, 26 parts being recovered. This product had a number average molecular weight of about 3,000, an acetylene content of 8.9%, and an aromatic to olefin proton ratio of 5.5:1.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])N(CCC)[C:4](=[O:49])[CH:3]=1.[CH2:50]([NH2:53])[CH2:51][CH3:52]>C(O)C>[CH2:50]([N:53]1[C:4](=[O:49])[CH:3]=[C:2]([NH:7][CH2:2][CH2:3][CH3:4])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]1=[O:45])[CH2:51][CH3:52]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCCN
Solvent: CCO
Product: CCCNc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 173.2 %

Procedure:
A solution of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (1.0 g) and propylamine (0.19 g) in ethanol (20 ml) was heated under reflux for 18 hours with stirring. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-dilute hydrochloric acid. The organic layer was washed with water, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow powders (0.58 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][CH2:10][O-:11].[Na+].CCO>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:11][CH2:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccnc(Cl)n1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 2,4-dichloropyrimidine (Aldrich, 10.0 g, 67.12 mmol) in abs. EtOH (120 mL) at -3° C. under nitrogen atmosphere was slowly added (over 2 hours) 1M NaOEt/EtOH (68 mL, 68 mmol) and the resulting mixture stirred for 1 hour. Solvent was evaporated in vacuo and the residue partitioned between H2O and Et2O. The aqueous phase was extracted with Et2O and the combined organic phase was washed with brine, dried (Na2SO4) and evaporated (water aspirator pump, 35° C.). The resulting residue was filtered and washed with petroleum ether to provide the desired product (8.05 g, 75%) as a yellowish solid: mp 30-31° C. (lit. 35° C.); 1H NMR (CDCl3): δ1.40 (t, J=7.2 Hz, 3H), 4.44 (quartet, J=7.2 Hz, 2H), 6.62 (d, J=5.7 Hz, 1H), 8.27 (d, J=5.7 Hz, 1H); MS m/z 161 (M+3, 34%), 159 (M+1, 100%). Anal. Calcd. for C6H7ClN2O: C, 45.44; H, 4.45; N, 17.66; Cl, 22.36. Found: C, 45.32; H, 4.41; N, 17.60; Cl, 22.43.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:16]=[N:17][CH:18]=2)[C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24](OCC)([O:28]CC)[O:25][CH2:26][CH3:27]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH:16]=[N:17][CH:18]=2)[C:14]=1[CH2:15][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:25][CH2:26][CH3:27])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)ccc2cncn12
Reactant: CCOC(CCCCBr)(OCC)OCC
Product: CCOC(=O)CCCCCc1c(OCc2ccccc2)ccc2cncn12

Procedure:
The condensation of 6-benzyloxy-5-methylimidazo[1,5-a]pyridine with 5-bromo-1,1,1-triethoxypentane essentially by the procedure described in Example 1 yields 6-benzyloxy-5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine; NMR (CDCl3) 1.4 (3H), 4.17 (2H), 4.97 (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]1=[O:14]
Reactant: O=C(O)CCCC(=O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C1CCCC(=O)C1c1ccccc1Cl
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A 500 ml round bottom flask was charged with 10.0 g (0.0416 mol) of 6-(2'-chlorophenyl)-5-ketohexanoic acid and 100 ml of 72% sulfuric acid. The reaction mixture was stirred and heated to 120° C. for 51/2 hours (oil bath), then poured into 600 ml of an ice water mixture. A tacky, white solid formed, and this was extracted into 300 ml of methylene chloride. The CH2Cl2 solution was washed six times with water, dried over anhydrous MgSO4 and stripped to leave 8.87 g of a tacky, white solid. This material was recrystallized from ethyl acetate to give 5.85 g (63%) of 2-(2'-chlorophenyl)-1,3-cyclohexanedione as a white, crystalline solid, m.p. 148.5°-149° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:25]1[CH2:26][CH2:27][N:22]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][CH2:24]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(NCCI)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of 6.92 g of N-benzyloxycarbonyl-2-iodo-ethylamine, 4.00 g of 1-benzylpiperazine, 15.66 g of potassium carbonate and 40 ml of hexamethylphosphoramide (HMPA) was stirred at room temperature for overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:methanol=15:1) to give 5.63 g of N-benzyloxycarbonyl-2-(4-benzylpiperazin-1-yl)ethylamine (yield: 70%, oily product, IR: 3230, 2910, 1710 cm-).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[C:19]2[C:28](=[C:29]([Cl:31])[CH:30]=1)[C:22]1([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[NH:21][C:20]2=[O:32]>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:28](=[C:29]([Cl:31])[CH:30]=1)[C:22]1([CH2:27][CH2:26][N:25]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:24][CH2:23]1)[NH:21][C:20]2=[O:32]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: O=C1NC2(CCNCC2)c2c(Cl)cc(Cl)cc21
Product: O=C1NC2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)c2c(Cl)cc(Cl)cc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 28 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 3 tR=1.312, min, m/z=471; 1H NMR (d6-DMSO) 1.38 (d, 2H), 2.37 (m, 1H), 2.60-2.80 (m, 2H), 2.83-3.02 (m, 3H), 3.35 (m, 2H), 3.94 (d, 1H), 4.51 (d, 1H), 7.38 (t, 1H), 7.55 (m, 2H), 7.64 (m, 2H), 7.80 (s, 1H), 9.88 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C>[Pd].C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A suspension of (4-(3-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (2.0 g, 9.0 mmol), 5 ml acetic acid and palladium on carbon (100 mg, 5%) in 50 ml ethanol was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered with the aid of celite. Crude (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 41%) was obtained after removing of solvents. A suspension of (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (0.2 g, 0.67 mmol), acetic acid (0.23 ml, 4.0 mmol) and 40% oxalaldehyde (0.14 ml, 1.0 mmol) in 40 ml acetonitrile was stirred at 50° C. under argon atmosphere overnight. The reaction was quenched with the 5 ml water and extracted with ethyl acetate (3×40 ml). The extraction was concentrated after drying over anhydrous sodium sulfate. Phenyl(4-(quinoxalin-6-yl)piperazin-1-yl)methanone (0.060 g, 28%) was obtained by flash column chromatograph (10% acetone in ethyl acetate). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.37 (d, br, 4H), 3.69 (s, br, 2H), 4.01 (s, br, 2H), 7.30 (d, J=2.7 Hz, 1H), 7.48 (m, 5H), 7.50 (dd, J=9.3, 2.7 Hz, 1H), 7.56 (d, J=9.3 Hz, 1H), 8.65 (d, J=1.9 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 49.1, 49.3, 110.8, 123.0, 127.6, 29.0, 130.4, 130.5, 1135.7, 139.0, 142.6, 144.9, 151.9, 145.6, 170.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)[N:6]=1.C1N=CN([C:24]([N:26]2[CH:30]=N[CH:28]=[CH:27]2)=[O:25])C=1.CNCC[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:18][C:4]1[S:3][C:2]([NH:1][C:24](=[O:25])[N:26]([CH2:27][CH2:28][CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:30])=[N:6][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(N)sc2Cl)cc1
Reactant: CNCCC(c1ccccc1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CN(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)cc2)c(Cl)s1
Temperature: 40 °C

Procedure:
To a mixture of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide 13 (0.100 g, 0.33 mmol), DMAP (0.056 g, 0.46 mmol), and CDI (0.085 g, 0.52 mmol) was added DMF (0.5 mL). The reaction mixture was heated to 40° C. for 13 h and N-methyl-3,3-diphenylpropan-1-amine 12 (0.111 g, 0.49 mmol) was added. The reaction mixture was heated to 40° C. for 2 d. Direct purification by flash column chromatography on silica gel (eluted with 10% to 50% EtOAc in DCM), followed by purification by flash column chromatography on silica gel (eluted with 1% to 5% MeOH in DCM) gave 3-(5-chloro-4-(4-(methylsulfonamido)-phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-methylurea 14 as a white foam. Mass spectrum: calculated for C27H27ClN4O3S2 554.2; found 555.2 (M++1).
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:7])[CH:18]=[CH:17][CH:16]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCCCC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(N)=O)c21

Procedure:
Using Method C above, 5-hexynamide (46 mg, 0.4 mmol) (prepared from 5-hexynoic acid by Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (113 mg, 0.31 mmol) using (Ph3P)2PdCl2 (12 mg) and Cul (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynamide. (Yield 52 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:30](O)=[O:31])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[Cl:29][C:24]1[CH:23]=[C:22]([N:18]2[C:19](=[O:21])[CH:20]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[C:16]([CH2:30][OH:31])=[N:17]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Cl)c(Cl)c3)nc2CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(3,4-dichlorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (from example 15 step A) (5 mg, 0.01 mmol) in THF (1 ml) at room temperature under argon was added 1 M BH3 in THF (31 uL, 0.031 mmol). The reaction mixture was stirred at room temperature for one hour. Methanol (2 mL) was carefully added to the reaction mixture and stirred at room temperature for two hours. Solvents were removed in vacuo. EtOAc (10 mL) and 1 N NaOH (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (10 mL), and brine (10 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give tert-butyl 4-(1-(3,4-dichlorophenyl)-3-(hydroxymethyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (2.3 mg, gum, 42.6%). 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.48 (m, 9H) 1.68-1.93 (m, J=3.95 Hz, 2H) 1.88-2.17 (m, 2H) 2.65-2.84 (m, 1H) 3.27-3.46 (m, 2H) 3.55-3.76 (m, 2H) 4.43-4.60 (m, 1H) 4.67 (s, 2H) 6.08-6.35 (m, 1H) 7.40-7.62 (m, 2H) 7.63-7.83 (m, 1H). MS (ESI) 414 (M+H-tBu).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[N:34]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35]1.C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[N:34]1([CH2:37][CH2:38][O:39][C:21]2[C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:19]([Cl:33])[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([C:10]4[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=4)[OH:9])[CH:17]=3)[N:22]=2)[CH2:36][CH2:35]1
Reactant: OCCN1CC1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OCCN3CC3)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), 2-(aziridin-1-yl)ethanol (16.2 μL, 0.20 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 20.2 mg, 0.51 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight, cooled and stirred at room temperature an additional night before workup. Reaction contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/MeOH) to afford the title compound. MS (ESI): mass calcd. for C30H26Cl2N4O2, 544.1; m/z found, 545.1 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.05 (d, J=2.0 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.61-7.57 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.31 (m, 1H), 7.28-7.23 (m, 6H), 6.18 (d, J=1.1 Hz, 1H), 4.51-4.44 (m, 2H), 3.37 (s, 3H), 2.50-2.39 (m, 2H), 1.48-1.37 (m, 2H), 0.97-0.94 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[O:32].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:32])[CH2:23][C:24]4([CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:29][C:30]3=[O:31])[CH2:3][CH2:2]2)=[N:8]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
Method A--A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (24.3 g., 0.11 mole) and 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7.9-dione (33.5 g., 0.11 mole), anhydrous potassium carbonate (32.4 g., 0.23 mole) and potassium iodide (3.9 g., 0.023 mole) in 1 liter of acetonitrile is stirred and heated under reflux for a period of 20 hr. The reaction mixture is filtered, concentrated in vacuo and residual material taken up in 350 ml. of chloroform which is filtered and concentrated in vacuo. The residue is triturated with ether, refrigerated and resulting solid collected. This material crystallized from acetonitrile (employing activated charcoal affords a first crop 25.1 g, m.p. 120°-124° C. and a second crop, 6.0 g, m.p. 123°-126° C. for a total yield of 31.1 g. (64% yield) of the free base form of the title compound. Crystallization from acetonitrile affords analytically pure 8-[4-[ 4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione, m.p. 124°-126° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:9]1[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1>>[CH:3]1([C:1]#[C:2][C:9]2[CH:10]=[C:11]([CH:15]([OH:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: C#CC1CCCC1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#CC2CCCC2)c1

Procedure:
Coupling of ethynylcyclopentane (40) with tert-butyl 3-(3-bromophenyl)-3-hydroxypropylcarbamate (39) following the method used in the synthesis of Example 13 gave tert-butyl 3-(3-(cyclopentylethynyl)phenyl)-3-hydroxypropylcarbamate (41) as a brown oil. Yield (0.386 g, 92%).
Reaction SMILES: [F:1][CH:2]([C:4]1[N:9]=[CH:8][NH:7][C:6](=[O:10])[CH:5]=1)[CH3:3].[I:11]Cl.II.ClCl>C(O)(=O)C>[F:1][CH:2]([C:4]1[N:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[I:11])[CH3:3]
Reactant: ClI
Reactant: CC(F)c1cc(=O)[nH]cn1
Agent: ClCl
Agent: II
Solvent: CC(=O)O
Product: CC(F)c1nc[nH]c(=O)c1I
Temperature: 25 °C

Procedure:
To an acetic acid (150 ml) solution of 6-(1fluoroethyl)-4-pyrimidone (56.8 g) was added dropwise under room temperature and stirring an acetic acid solution of iodine monochloride prepared by adding iodine (50.8 g) to acetic acid (500 ml) and blowing chlorine (15 g) thereinto under room temperature and stirring, and the resulting mixture was stirred for 6 hours.